Dataset Information

Novel Carboxylated Chitosan-Based Triptolide Conjugate for the Treatment of Rheumatoid Arthritis.

ABSTRACT: A new platform for triptolide (TP) delivery was prepared by conjugating TP to a carboxylmethyl chitosan (CMCS). Compared with the natural TP, the TP-conjugate (TP-CMCS) containing TP of ~5 wt% exhibited excellent aqueous solubility (> 5 mg/mL). Results of in vitro experiments showed that TP-CMCS could relieve TP-induced inhibition on RAW264.7 cells and apoptosis, respectively. Compared with the TP group, TP-CMCS could effectively alleviate the toxicity injury of TP and decreased the mortality rate of the mice (p < 0.05). TP-CMCS did not cause much damage to the liver (AST and ALT) and kidney (BUN and CRE) (p < 0.05). After administration, the levels of IL-6, IL-1β, and TNF-α decreased, and the arthritis detumescence percentages increased significantly, and the bony erosion degree was distinctly decreased in the TP-CMCS groups and TP group. Our results suggested that TP-CMCS was a useful carrier for the treatment of RA, which enhanced aqueous solubility of free TP and reduced drug toxicity in vitro and in vivo.

SUBMITTER: Zhang L

PROVIDER: S-EPMC7150988 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Novel Carboxylated Chitosan-Based Triptolide Conjugate for the Treatment of Rheumatoid Arthritis.

Zhang Lan L Yan Min M Chen Kun K Tian Qikang Q Song Junying J Zhang Zijuan Z Xie Zhishen Z Yuan Yong Y Jia Yaquan Y Zhu Xin X Zhang Zhenqiang Z Wu Xiangxiang X Zeng Huahui H

Pharmaceutics 20200226 3

A new platform for triptolide (TP) delivery was prepared by conjugating TP to a carboxylmethyl chitosan (CMCS). Compared with the natural TP, the TP-conjugate (TP-CMCS) containing TP of ~5 wt% exhibited excellent aqueous solubility (> 5 mg/mL). Results of in vitro experiments showed that TP-CMCS could relieve TP-induced inhibition on RAW264.7 cells and apoptosis, respectively. Compared with the TP group, TP-CMCS could effectively alleviate the toxicity injury of TP and decreased the mortality ra ...[more]

PMID: 32110979

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Project description:BackgroundRheumatoid arthritis (RA) tends to occur in symmetrical joints and is always accompanied by synovial hyperplasia and cartilage damage. Triptolide (TP), an extract from Tripterygium, has anti-inflammatory and immunomodulatory properties and could be used in the treatment of RA. However, its poor water solubility and the multi-system lesions caused by the use of this substance limit its clinical application. Therefore, it would be of great significance to assemble a composite nanoparticle hydrogel and apply it to a collagen-induced arthritis (CIA) mouse model to investigate the therapeutic effect and biosafety of this compound.MethodTP@HSA nanoparticles (TP@HSA NPs) were fabricated with a self-assembly method; a thermosensitive hydrogel loaded with the TP@HSA NPs (TP@HSA NP hydrogel) was prepared by using chitosan and beta- glycerophosphate (β-GP) and was then intra-articularly injected into CIA mice. The changes in joint swelling were measured with a digital caliper, and inflammation and cartilage damage were evaluated by using hematoxylin and eosin (H&E) and safranin O-fast green (SO&FG) staining, respectively.ResultsTP@HSA NPs with an average diameter of 112 ± 2 nm were successfully assembled, and their encapsulation efficiency and drug loading efficiency were 47.6 ± 1.5% and 10.6 ± 3.3%, respectively. The TP@HSA NP hydrogel had a gelation temperature of 30.5 ± 0.2 °C, which allows for its injection at low temperatures and its sol-gel transformation under physiological conditions within 2 min, making it a suitable drug depot. The TP@HSA NP hydrogel was intra-articularly injected into CIA mice; it released TP locally and exerted anti-inflammatory and immunomodulatory effects, alleviating synovial inflammation and cartilage damage effectively.ConclusionsWe successfully fabricated a TP@HSA NP-loaded thermosensitive hydrogel with good biosafety, which can release TP slowly for the treatment of RA. Our study provides a basis for the development of TP-based innovative preparations and has good application prospects.

Project description:Triptolide (TP), a major active component of the herb Tripterygium wilfordii Hook F (TwHF), has been shown to exert therapeutic potential against rheumatoid arthritis (RA). However, its molecular mechanism of action has not been fully elucidated. This study aimed to analyze the potential target of TP based on the discovery of differentially methylated and expressed genes (DMEGs) in RA using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq). Five RA samples and ten control samples were obtained from China-Japan Friendship Hospital. The various levels of m6A methylation and genes expressed in the RA and control groups were compared by MeRIP-seq and RNA-seq. Bioinformatics explorations were also performed to explore the enriched biological roles and paths of the differentially expressed m6A methylation and genes. Molecular networks between TP target proteins and DMEGs were performed using Ingenuity Pathway Analysis (IPA) software. Potential target of TP was determined with Gene Expression Omnibus (GEO) database mining, molecular docking, and in vitro experiment validation. In total, 583 dysregulated m6A peaks, of which 295 were greatly upregulated and 288 were greatly downregulated, were identified. Similarly, 1,570 differentially expressed genes were identified by RNA-seq, including 539 upregulated and 1,031 downregulated genes. According to the deeper joint exploration, the m6A methylation and mRNA expression degrees of 35 genes varied greatly. Molecular networks between TP target proteins and DMEGs were constructed, and the results revealed that tubulin beta-2A chain (TUBB2A), insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1), and FOS-like 1 (FOSL1) were the most relevant genes that correlated with the target proteins of TP. The results of the GEO database showed that the gene expression of IGF2BP3 was increased in RA synovial tissue and consistent with the trend of our sequencing results of RA PBMCs. Molecular docking and in vitro experiment suggested that TP and IGF2BP3 had a high binding affinity and TP could decrease the mRNA expression of IGF2BP3 in PBMCs and MH7A.This research established a transcriptional map of m6A in RA PBMCs and displayed the hidden association between RNA methylation alterations and associated genes in RA. IGF2BP3 might be a potential therapeutic target of TP during RA treatment.

Project description:Triptolide (TP), an active component isolated from Tripterygiumwilfordii Hook F, has therapeutic potential against rheumatoid arthritis (RA). However, the underlying molecular mechanism has not been fully elucidated. The aim of this study is to investigate the mechanisms of TP acting on RA by combining bioinformatics analysis with experiment validation. The human protein targets of TP and the human genes of RA were found in the PubChem database and NCBI, respectively. These two dataset were then imported into Ingenuity Pathway Analysis (IPA) software online, and then the molecular network of TP on RA could be set up and analyzed. After that, both in vitro and in vivo experiments were done to further verify the prediction. The results indicated that the main canonical signal pathways of TP protein targets networks were mainly centered on cytokine and cellular immune signaling, and triggering receptors expressed on myeloid cells (TREM)-1 signaling was searched to be the top one shared signaling pathway and involved in the cytokine and cellular immune signaling. Further in vitro experiments indicated that TP not only remarkably lowered the levels of TREM-1 and DNAX-associated protein (DAP)12, but also significantly suppressed the activation of janus activating kinase (JAK)2 and signal transducers and activators of transcription (STAT)3. The expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in lipopolysaccharides (LPS)-stimulated U937 cells also decreased after treatment with TP. Furthermore, TREM-1 knockdown was able to interfere with the inhibition effects of TP on these cytokines production. In vivo experiments showed that TP not only significantly inhibited the TREM-1 mRNA and DAP12 mRNA expression, and activation of JAK2 and STAT3 in ankle of rats with collagen-induced arthritis (CIA), but also remarkably decreased production of TNF-α, IL-1β and IL-6 in serum and joint. These findings demonstrated that TP could modulate the TREM1 signal pathway to inhibit the inflammatory response in RA.

Dataset Information

Novel Carboxylated Chitosan-Based Triptolide Conjugate for the Treatment of Rheumatoid Arthritis.

Publications

Novel Carboxylated Chitosan-Based Triptolide Conjugate for the Treatment of Rheumatoid Arthritis.

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